Bladder cancer is the most common cancer of the urinary tract. Bladder cancer affects men more than three times more frequently than women. It is the seventh most commonly diagnosed type of cancer in men (Ferlay et al., 2013). Approximately 75-85% of patients with newly-diagnosed bladder cancer show non-muscle-invasive bladder tumors, i.e., tumors that are limited to the mucous membrane. In this case, the tumor stages are carcinoma in situ (Tis), Ta, or T1 (Babjuk et al., 2015). The rates of recurrence in the case of non-muscle-invasive bladder carcinoma are very high. The probability of recurrence is approximately 15 to 61% within the first year and 31 to 78% after 5 years (Witjes, Douglass, 2007). The high rates of recurrence require a year-long monitoring and follow-up of once-diseased patients.
The most common symptom of non-muscle-invasive bladder cancer is hematuria. In addition, irritating symptoms or pains in the lower urinary tract can also occur. A physical study does not provide any information about a potential non-muscle-invasive bladder tumor (Babjuk et al., 2015). The visual inspection of the bladder with an endoscope and white-light illumination (white-light cystoscopy) and a removal of tissue samples represents a first diagnosis. This method is reliable for exophytic tumors. Flat carcinomas (in particular Tis), dysplasia, multifocal growth, and microscopic lesions are very much more difficult to detect and are often overlooked during white-light cystoscopy.
The method of fluorescence cystoscopy (also referred to as photodynamic diagnosis (PDD)) improves the detection rates of non-muscle-invasive bladder cancer, in particular of Tis, and thus reduces the recurrence rate (Burger et al., 2013; Kausch et al., 2010; Stenzel et al., 2010).
The photodynamic diagnosis (PDD) uses the photoactive properties of certain compounds, so-called photosensitizers, which preferably accumulate in tumor tissue and improve the optical delineation between normal and neoplastic tissue.
The basic principle of the photodynamic diagnosis (PDD) is based on a two-step method, comprising a systemic or topical application of a photosensitizer, and the activation of the photosensitizer by irradiation with visible light with a suitable wavelength.
The “gold standard” in the detection of non-muscle-invasive bladder cancer is white-light cystoscopy. Upon suspicion of Tis, however, the use of fluorescence cystoscopy is recommended (Babjuk et al., 2015), by which on average 20% more Tis can be found (Witjes et al., 2010).
The porphyrin precursor 5-aminolevulinic acid (5-ALA) and the derivative hexaminolevulinic acid (HAL) are used in fluorescence diagnosis. Both substances are pro-drugs. By metabolizing the pro-drug, a photoactive molecule is produced, which is used for PDD. The only substance approved as a pharmaceutical agent for PDD in the indication of bladder carcinoma is hexaminolevulinic acid (Hexvix®, Cysview®).
The properties of hypericin (1,3,4,6,8,13-hexahydroxy-10,11-dimethylphenanthro (1,10,9,8-opqra) perylene-7,14-dione) as a photosensitizer and indicator for cancer cells, especially for detection of non-muscle-invasive tumors of the urothelium, are known. Hypericin is not a pro-drug and must not be metabolized in the tissue, but rather can be stimulated directly with light with a suitable wavelength, as soon as the hypericin has accumulated in the tissue.
However, pure hypericin is hydrophobic and water-insoluble. For this reason, in the past in preclinical studies, a water-soluble polymer, polyethylene glycol (PEG), or in clinical studies, serum proteins were used as effective hypericin transporters/carriers in order to bring the insoluble hypericin into the target cells (D'Hallewin et al., 2000 and 2002; Olivo et al., 2003; Pytel et al., 2002).
The solubility of hypericin can be increased by the presence of the adjuvant polyvinylpyrrolidone (“povidone,” PVP) (WO 01/89576 A2).
A formulation that consists of 25 mg of PVP and 0.25 mg of hypericin was clinically studied in 57 patients (Kubin et al., 2008). With respect to flat lesions (Tis and dysplasia), a detection rate of 100% for Tis and 85% for dysplasia was achieved on the lesion level with PVP-hypericin-supported PDD, while only 33% (Tis) and 31% (dysplasia) were detected under white-light cystoscopy.
The improved detection on the lesion level is also evident on the patient level: in the case of 16% of the patients, the PVP-hypericin detects supported PDD lesions that were overlooked in white-light cystoscopy. The instillation time (dwell time in the bladder) of the PVP-hypericin solution was approximately 60-220 minutes (on average, 111±39 (SD) minutes) (Kubin et al., 2008).
Even when the known PDD study has achieved good results, a serious problem remains unsolved. The long instillation time (i.e., the retaining of the administered solution in the patient's bladder) of at least 60 minutes represents a burden for patients with non-muscle-invasive bladder carcinoma, who very often suffer from pains or cramps.